This report describes a Drosophila model of ichthyosis using mutations of the Drosophila gene osy. This gene encodes a member of the ABCH ATP-binding cassette transporter subfamily. Dmel\osy is a low-scoring ortholog of multiple human genes, however, all have higher-scoring orthologs in Drosophila. There are multiple types of congenital autosomal recessive ichthyosis linked to one of the related human genes, ABCA12 (MIM:607800, MIM:601277), including a rare severe form known as harlequin ichthyosis (MIM:242500).
The human ABCA12 gene has not been introduced into Drosophila.
In an RNAi screen for cuticular defects, the osy knockdown phenotypes was identified as being similar to the effects on humans of homozygous and compound heterozygous mutations in ABCA12. Several alleles have been generated for osy, including alleles carrying RNAi targeting constructs and alleles generated by insertional mutagenesis. Larvae with ubiquitously reduced osy dessicate and die shortly after hatching. Applying halocarbon oil to the larva extends lifespan. Tissue-specific knockdown of osy in the wing causes a lack of cuticular hydrocarbons on the wing cuticle, and abnormal accumulation of lipids in the epidermis.
[updated Mar. 2021 by FlyBase; FBrf0222196]
Harlequin ichthyosis (HI) is a rare, severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an "armor" of thick scale plates separated by deep fissures. There is bilateral ectropion and eclabium, and the nose and ears are flattened and appear rudimentary. Constricting bands around the extremities can restrict movement and cause digital necrosis. As the skin barrier is severely compromised, neonates are more prone to sepsis, dehydration, and impaired thermoregulation. Babies who survive into infancy and beyond develop skin changes resembling severe nonbullous congenital ichthyosiform erythroderma (NBCIE). (From Rajpopat et al. 2011 and references therein, pubmed:21339420.)
ABCA12 mutations were identified in 38 of 45 harlequin ichthyosis patients. Patients with mutations were classified as homozygous if both alleles carried the same mutation (n = 27) or compound heterozygous, indicating that different mutations were seen on each allele (n = 11). All the deaths were associated with homozygous mutations. Among the mutations found in 21 survivors, 11 (52%) were compound heterozygous and 10 (48%) were homozygous. (From Wang et al. 2020, FBrf0244656.)
In mammals, the stratum corneum, which is the uppermost skin layer, consists of corneocytes and a composite lipid-rich matrix including ceramides that are either free or bound to so-called cornified envelope proteins. A number of ceramide-producing and transporting enzymes have been identified to participate in the formation of the lipid matrix. A key player in this process is the ATP-binding cassette transporter A12 (ABCA12) that loads ceramides into specialized secretory vesicles the so-called lamellar granules before they are deposited into the extracellular space. ABCA12 dysfunction through mutations in the respective gene leads to the failure to form the ceramide matrix, thereby causing different types of congenital ichthyosis that are associated with excessive transepidermal water loss, impaired thermoregulation and enhanced infection sensitivity in mice and humans. (From Wang et al. 2020 and references therein, FBrf0244656.)
Dmel\osy encodes a member of the ABCH subfamily of the ATP-binding cassette (ABC) transporter family. Members of the ABC transporter family are primary active transporters that use ATP hydrolysis to drive the transport of substrates across the membrane; the ABCH subfamily are half transporters and must dimerize to form a functional transporter. Genes of the ABCH subfamily are found in arthropods, but not in fungi, plants or mammals (FlyBase, FBgg0000550).
Low-scoring ortholog of several ABCA genes in human; many similar genes in both species.
